5-HT2 receptors have low affinity for serotonin (5-HT) and do not show receptor supersensitivity following lesion of nerve ending. We have proposed for the existence of an endogenous ligand (endocoid) for this receptor site. Our previous studies have demonstrated that some protein fractions derived from bovine and rat brains display activity of inhibiting 3H-ketanserin binding but inhibiting only slightly 3H-mianserin binding to rat brain membrane. This protein (Mr=6000) has been partially purified by gel filtration and HPLC column chromatography. The present report shows that rat brain striatum contained an unique 3H-ketanserin recognition site which was insensitive to mianserin and could be the receptor site for this putative endocoid. Radioligand binding assays disclosed high and low affinity ketanserin binding sites in the rat striatum. Only the high affinity sites were inhibited with nanomolar affinity by classical 5-HT2 antagonist and showed up-regulation by chronic p-chloro-phenylalanine treatment. Autoradiographic studies showed that mianserin (100 nM) displaced only the binding of 3H-ketanserin to the cortex and septum but not that to the striatum. Perhaps these mianserin-resistent ketanserin sites represent the receptor for this or some yet undiscovered peptide. The present finding might have clinical implication for the etiology of affective disorders.